Inflammatory Biomarkers for Persistent Fatigue in Breast Cancer Survivors

Purpose: This study seeks to define immunologic and inflammatory variables associated with persistent post-treatment fatigue in breast cancer survivors. Experimental Design: Leukocyte subsets, plasma inflammatory markers, and ex vivo proinflammatory cytokine production were assessed in 50 fatigued a...

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Bibliographic Details
Published in:Clinical cancer research 2006-05, Vol.12 (9), p.2759-2766
Main Authors: COLLADO-HIDALGO, Alicia, BOWER, Julienne E, GANZ, Patricia A, COLE, Steve W, IRWIN, Michael R
Format: Article
Language:English
Subjects:
Antineoplastic agents
Biological and medical sciences
Biomarkers - blood
breast cancer survivor
Breast Neoplasms - physiopathology
CD4-Positive T-Lymphocytes - immunology
CD8-Positive T-Lymphocytes - immunology
Cytokines - blood
fatigue
Fatigue - physiopathology
Female
Gynecology. Andrology. Obstetrics
Humans
IL-6
Inflammation
Lymphocyte Count
Mammary gland diseases
Medical sciences
Middle Aged
Pharmacology. Drug treatments
Survivors
Tumors
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Summary:Purpose: This study seeks to define immunologic and inflammatory variables associated with persistent post-treatment fatigue in breast cancer survivors. Experimental Design: Leukocyte subsets, plasma inflammatory markers, and ex vivo proinflammatory cytokine production were assessed in 50 fatigued and nonfatigued breast cancer survivors recruited ≥2 years after successful primary therapy. Multivariate statistical analyses were used to define a composite immunologic biomarker of fatigue risk. Results: Fatigued breast cancer survivors were distinguished from nonfatigued survivors by increased ex vivo monocyte production of interleukin (IL)-6 and tumor necrosis factor-α following lipopolysaccharide stimulation, elevated plasma IL-1ra and soluble IL-6 receptor (sIL-6R/CD126), decreased monocyte cell-surface IL-6R, and decreased frequencies of activated T lymphocytes and myeloid dendritic cells in peripheral blood (all P < 0.05). An inverse correlation between sIL-6R and cell-surface IL-6R was consistent with inflammation-mediated shedding of IL-6R, and in vitro studies confirmed that proinflammatory cytokines induced such shedding. Multivariate linear discriminant function analysis identified two immunologic markers, the ratio of sIL-6R to monocyte-associated IL-6R and decreased circulating CD69 + T lymphocytes, as highly diagnostic of fatigue ( P = 0.0005), with cross-validation estimates indicating 87% classification accuracy (sensitivity = 0.83; specificity = 0.83). Conclusion: These results extend links between fatigue and inflammatory markers to show a functional alteration in proinflammatory cytokine response to lipopolysaccharide and define a prognostic biomarker of behavioral fatigue.
ISSN:1078-0432
1557-3265
DOI:10.1158/1078-0432.CCR-05-2398